Blood-Based Molecular Clock Biomarkers Predict Acute Ischemic Stroke Onset: A Prospective Observational Study

NCT07453277 | Active Not Recruiting DMC

• 1 other identifier: IZMIR-KCU-02
• Study Type: observational
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

Acute ischemic stroke (AIS) is a major cause of mortality and long-term neurological disability worldwide. The effectiveness of reperfusion therapies such as intravenous thrombolysis and mechanical thrombectomy is highly dependent on the time elapsed since symptom onset. However, in approximately 15-25% of patients, the exact onset time cannot be determined because symptoms begin during sleep (wake-up stroke) or the onset is otherwise unclear. This uncertainty often prevents patients from receiving time-dependent reperfusion treatments. Currently, imaging-based approaches such as diffusion-weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch are used to estimate the biological stage of ischemia in patients with unknown onset time. However, advanced imaging techniques may not be available in all centers and interpretation may vary. This study aims to evaluate the diagnostic performance of a multi-biomarker panel representing different biological components of ischemic brain injury, including glial, neuronal, axonal, cellular stress, and vascular responses. Blood samples obtained at admission will be analyzed for glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCH-L1), serum neurofilament light chain (sNfL), phosphatidylethanolamine-binding protein 1 (PEBP1), and matrix metalloproteinase-9 (MMP-9). The primary objective is to determine whether this biomarker panel can distinguish patients presenting within ≤4.5 hours from those presenting after \>4.5 hours of symptom onset. Biomarker findings will be compared with imaging-based reference methods to explore the feasibility of a blood-based "molecular clock" approach for estimating stroke timing in patients with uncertain onset.

Conditions

Emergency Medicine; Stroke Acute

Keywords

molecular clock biomarkers; wake up stroke; acute stroke

Outcome Measures

Primary Outcomes (1)

• Diagnostic performance of the multi-biomarker panel in identifying the biological time window of acute ischemic stroke (≤4.5 hours vs >4.5 hours from symptom onset)

  The primary outcome will be the ability of the combined biomarker panel (GFAP, UCH-L1, sNfL, PEBP1, and MMP-9) measured from admission blood samples to discriminate patients presenting within ≤4.5 hours versus \>4.5 hours after symptom onset. Diagnostic performance will be evaluated using receiver operating characteristic (ROC) curve analysis and reported as area under the curve (AUC), sensitivity, specificity, and optimal cut-off values.

  At emergency department admission.

Secondary Outcomes (4)

• Diagnostic performance of individual biomarkers

  At emergency department admission.

• Association between biomarker levels and imaging-based reference methods

  Baseline imaging obtained at hospital admission.

• Incremental diagnostic value of the combined biomarker model

  At emergency department admission.

• Correlation between circulating biomarker levels and infarct volume on diffusion-weighted imaging (DWI)

  Baseline imaging obtained within the initial diagnostic evaluation after hospital admission.

Study Arms (2)

ACUTE STROKE PRESENTING TO THE EMERGENCY DEPARTMENT-1

ACUTE STROKE PRESENTING TO THE EMERGENCY DEPARTMENT (WITNESSED STROKE, STROKE WITH KNOWN OCCURRENCE)

ACUTE WAKE UP STROKE PRESENTING TO THE EMERGENCY DEPARTMENT-2

WAKE UP STROKE (Without Witnesses and Unknown Start Time)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Patients with acute ischemic stroke whose onset time is unknown or who present with a wake-up stroke. Serum/plasma samples obtained from venous blood samples taken during routine clinical practice in all patients will be analyzed for GFAP, UCH-L1, sNfL, PEBP1, and MMP-9 levels. Patients' demographic data, clinical characteristics, NIHSS scores, and magnetic resonance imaging (MRI) findings (particularly DWI-FLAIR mismatch status) will be recorded from the electronic patient record system. The performance of the multi-compartment molecular panel formed by the obtained biomarker levels in distinguishing the biological time window of acute ischemic stroke (≤4.5 hours vs. \>4.5 hours) will be evaluated by comparing it with the imaging-based reference method.

You may qualify if:

• Be 18 years of age or older
• Presence of acute focal neurological deficit
• Presentation within ≤24 hours of the last time the patient was well

You may not qualify if:

• Intracranial hemorrhage
• Active infection or sepsis
• Major surgery/trauma within the last 14 days
• Active autoimmune disease
• Stroke within the last 3 months
• Immunosuppressive therapy

Sponsors & Collaborators

• Izmir Katip Celebi University: lead

Study Sites (1)

Izmir Katip Çelebi University Ataturk Research and Training Hospital

Izmir, 35220, Turkey (Türkiye)

Location

Related Publications (5)

• Simats A, Ramiro L, Garcia-Berrocoso T, Brianso F, Gonzalo R, Martin L, Sabe A, Gill N, Penalba A, Colome N, Sanchez A, Canals F, Bustamante A, Rosell A, Montaner J. A Mouse Brain-based Multi-omics Integrative Approach Reveals Potential Blood Biomarkers for Ischemic Stroke. Mol Cell Proteomics. 2020 Dec;19(12):1921-1936. doi: 10.1074/mcp.RA120.002283. Epub 2020 Aug 31.

  PMID: 32868372 BACKGROUND

• Liu F, Chen C, Chen C, Parsons MW, Li G, Lin L; INSPIRE Study Group. Salvageable Time Window: Tissue Clock After Acute Ischemic Stroke Onset. Stroke. 2025 Nov;56(11):3165-3174. doi: 10.1161/STROKEAHA.125.051780. Epub 2025 Aug 7.

  PMID: 40772304 BACKGROUND

• Zhang YL, Zhang JF, Wang XX, Wang Y, Anderson CS, Wu YC. Wake-up stroke: imaging-based diagnosis and recanalization therapy. J Neurol. 2021 Nov;268(11):4002-4012. doi: 10.1007/s00415-020-10055-7. Epub 2020 Jul 15.

  PMID: 32671526 BACKGROUND

• Ho JP, Powers WJ. Contemporary Management of Acute Ischemic Stroke. Annu Rev Med. 2025 Jan;76(1):417-429. doi: 10.1146/annurev-med-050823-094312. Epub 2025 Jan 16.

  PMID: 39496213 BACKGROUND

• Zhu F, Wang Z, Song J, Ji Y. Correlation analysis of inflammatory markers with the short-term prognosis of acute ischaemic stroke. Sci Rep. 2024 Aug 1;14(1):17772. doi: 10.1038/s41598-024-66279-4.

  PMID: 39090131 BACKGROUND

Biospecimen

Retention: SAMPLES WITHOUT DNA

Serum of the patient in first admission to the EM

MeSH Terms

Conditions

Stroke; Ischemic Stroke

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Study Officials

• BORA, MD PhD

  Izmir Katip Çelebi University Faculty of Medicine

  STUDY DIRECTOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: March 1, 2026
• First Posted: March 5, 2026
• Study Start: March 1, 2026
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): April 1, 2027
• Last Updated: March 6, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

TU (1)